This R21 application is aimed to develop an approach that combines a novel in vivo imaging technique, diffusion tensor imaging (DTI), and physiological and cognitive measures to investigate the relationship between vascular comorbidities and white matter damage in patients with mild-moderate Alzheimer's disease (AD). Vascular comorbidities such as hypertension, hypercholesterolemia, and cardiac disease are common in AD patients, and have been found in studies of normal aging and dementia to be related to both cognitive dysfunction and white matter (WM) damage. Although a handful of studies have examined WM changes in AD patients using DTI, these studies have included relatively healthy patients without vascular comorbidities and/or cerebrovascular changes, and therefore have not yet examined their association. In addition, general measures of overall cognitive functioning have been used as opposed to domain-specific tests that are necessary to evaluate associated deficits. A total of 50 AD patients and 20 cognitively intact controls will be prospectively recruited and will undergo objective measurement of vascular comorbidities, neuroimaging studies using DTI, and neuropsychological evaluations. Innovative aspects of this proposed R21 project are 1) to further develop DTI methodology to quantify WM damage and its relationship to vascular comorbidity in AD patients, and 2) to identify brain regions and corresponding cognitive deficits that are vulnerable to vascular comorbidities. Specific Aims are 1) To investigate the relationship between vascular comorbidities and DTI indices of white matter integrity in patients with mild-moderate AD. 2) To identify specific white matter regions which are vulnerable to the presence and severity of vascular comorbidities in AD patients and 3) To test and validate DTI indices in specific brain regions by correlating them with neurocognitive performance. The findings are anticipated to alert health care professionals to the importance of vascular comorbidities and their control in patients with Alzheimer's disease. An overriding accomplishment will be the delineation of specific DTI parameters which can be used as markers of disease progression and treatment efficacy. Since vascular comorbidities are potentially treatable, the findings of this study will alert clinicians to the importance of measuring and controlling these comorbidities, even in patients who are already diagnosed with Alzheimer's disease. It is anticipated that the findings will help clarify the overlap between AD and vascular dementia, identify at risk patients, and contribute to the development of pharmacologic agents that target specific patient subgroups. [unreadable] [unreadable] [unreadable]